Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth

Chiara V. Ragni, Nicolas Diguet, Jean-François Le Garrec, Marta Novotova, Tatiana P. Resende, Sorin Pop, Nicolas Charon, Laurent Guillemot, Lisa Kitasato, Caroline Badouel, Alexandre Dufour, Jean-Christophe Olivo-Marin, Alain Trouvé, Helen McNeill and Sigolène M Meilhac ()
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Chiara V. Ragni: Institut Pasteur
Nicolas Diguet: Institut Pasteur
Jean-François Le Garrec: Institut Pasteur
Marta Novotova: Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences
Tatiana P. Resende: Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto
Sorin Pop: Institut Pasteur, Quantitative Image Analysis Unit
Nicolas Charon: ENS Cachan, Center of Mathematics and Their Applications
Laurent Guillemot: Institut Pasteur
Lisa Kitasato: Present address: Imagine-Institut Pasteur, Laboratory of Heart Morphogenesis, INSERM UMR1163, 75015 Paris, France
Caroline Badouel: Samuel Lunenfeld Research Institute, Mt Sinai Hospital
Alexandre Dufour: Institut Pasteur, Quantitative Image Analysis Unit
Jean-Christophe Olivo-Marin: Institut Pasteur, Quantitative Image Analysis Unit
Alain Trouvé: ENS Cachan, Center of Mathematics and Their Applications
Helen McNeill: Samuel Lunenfeld Research Institute, Mt Sinai Hospital
Sigolène M Meilhac: Institut Pasteur

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Although in flies the atypical cadherin Fat is an upstream regulator of Hippo signalling, the closest mammalian homologue, Fat4, has been shown to regulate tissue polarity rather than growth. Here we show in the mouse heart that Fat4 modulates Hippo signalling to restrict growth. Fat4 mutant myocardium is thicker, with increased cardiomyocyte size and proliferation, and this is mediated by an upregulation of the transcriptional activity of Yap1, an effector of the Hippo pathway. Fat4 is not required for the canonical activation of Hippo kinases but it sequesters a partner of Yap1, Amotl1, out of the nucleus. The nuclear translocation of Amotl1 is accompanied by Yap1 to promote cardiomyocyte proliferation. We, therefore, identify Amotl1, which is not present in flies, as a mammalian intermediate for non-canonical Hippo signalling, downstream of Fat4. This work uncovers a mechanism for the restriction of heart growth at birth, a process which impedes the regenerative potential of the mammalian heart.

Date: 2017
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DOI: 10.1038/ncomms14582

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